4H-Imidazo{8 1,2-a{9 {8 1,4{9 benzodiazepines

ABSTRACT

6-Phenyl-4H-imidazo(1,2-a)(1,4)benzodiazepines of the formula XXIV:   wherein R0, R1, and R2 are hydrogen, methyl, or ethyl; wherein R3 is hydrogen, chloro, or fluoro; wherein R4 is hydrogen or fluoro; wherein R5 is hydrogen, chloro, fluoro, bromo, trifluoromethyl, or nitro; and wherein R&#39;&#39; and R&#39;&#39;&#39;&#39; are hydrogen or alkyl of from one to three carbon atoms, anxiolytic activity and are suitable for the treatment of mammals and birds.

United States Patent [1 1 Gal] [ 1 4H-IMIDAZO1 1,2-

A 1,4]BENZODIAZEPINES [75] Inventor: Martin Gall, Kalamazoo, Mich.

{73] Assignee: The Upjohn Company, Kaildmazoq Michv [22] Filed: Sept. 12, I974 [2]] App]. No; 505,342

OTHER PUBLICATIONS Hester et aL, Chem. Abst. 1973, Vol. 78, Nov 136353k. Derieg et ul, Chem. Abst. 1973, Vol. 79, No. 9229814.

Primary Examiner-Natalie Trousoe Attorney. Agent, or Firm Hans L. Berneis 1 Oct. 7, 1975 [57] ABSTRACT the formula XXIV:

XXIV

wherein R R and R are hydrogen. methyl, or ethyl; wherein R:, is hydrogen. ehloro, or fluoro; wherein R, is hydrogen or fluoro; wherein R is hydrogen. chloro. fluoro, bromo, trifluoromethyl 0r nitro; and wherein R and R" are hydrogen or alkyl of from one to three carbon atoms, anxiolytic activity and are suitable for the treatment of mammals and birds.

ll Claims, N0 Drawings 1 2 4I-I-IMIDAZO[ 1 ,Z-A I ,41BENZODIAZEPINES Q M BACKGROUND OF THE INVENTION HzN-C N FIELD OF THE INVENTION 5 H This invention is directed to new organic compounds and is particularly concerned with novel 6-phenyI- 4Himidazo[ I,2-a] 1,4]benzodiazepines, novel inter- R mediates and processes for the production thereof. N

The novel compounds and the processes of producw R5 tion therefor can be illustratively represented as follows: R H

Scheme l I V 4 H I5 N J/ 2 R O N R 1 P6 R' l N-C R 8 I H Q N I 5 R3 XXI V A i R4 2 c R0 Alternatively, the synthetic steps for compound V can H H be carried out as follows: i Scheme l I S Q I 2 H R5 I l R2 4 R R1 W R H I H Ro l B rC C C N H R5 I R5 N R1 H I 5 a I R g N3C\CC/ h H 2 VII N Rs H 1 R T K ,0 l/ NH2 'C C /R2 N w l R5 Scheme I I The regents used in the foregoing syntheses were prepared (for scheme 1) by the method shown below:

/ pounds IV and V represent the partial scope of the fi- CH nal, desired compounds, otherwise identified as com pounds of formula XXIV.

H C C H-N In a similar manner the desired final compounds can XXI l I be prepared by reacting compound I with the interme- CH3 diate compound XVIII to give compound VI; reacting 0 1 compound VI with sodium azide to give compound VII; catalytically hydrogenating VII to give compound VIII; wherein R R and R are hydrogen, methyl or ethyl; alkylating to give compound IX, and then heating comwherein R is hydrogen, chloro or fluoro; wherein R is pound IX to between I IOC and 200C to give comhydrogen or fluoro; wherein R is hydrogen, chloro, pound V, which is a final compound of the invention, fluoro, bromo, trifluoromethyl or nitro; and wherein R encompassed by formula XXIV. Compound VII may and R are hydrogen. methyl or ethyl. be prepared directly by reacting compound I with the The more preferred compounds of this invention intermediate compound XX. Compound IX may also have the formula XXIVB: l5 be prepared directly by reacting compound I with the intermediate XXIII (scheme III).

Other variations of these reaction schemes are possi- R ble, and will appear in examples. The examples will also N-CH2 show the production of the reactants used in this invention.

The new final compounds of formula XXIV and the pharmaeologically acceptable acid addition salts thereof are essentially products which are useful in mammals to counteract anxiety and to produce tranquilization.

' 3 DESCRIPTION OF THE PREFERRED EMBODIMENT OF THE INVENTION XXVB The tranquilization and sedative activity of the new compounds of formula XXIV and their pharmacologically acceptable acid addition salts was tested in mice as follows: wherein R R and R are hydrogen or methyl, Chimney test: [Med Exp. 4, 145 (1961)]: The test wherein R and R are defined as above; and wherein determines the ability of mice to back up and out 's i5 chloro. fiuol'o 0T r fl me hyl. n the P of a vertical glass cylinder within 30 seconds. At macologically acceptable acid addition salts thereof. the effective dosage, 50% of the mice failed doing The most preferred compounds are of the formula it. XXIVC: Dish test: Mice in Petri dishes (10 cm. diameter, 5 cm. high, partially embedded in wood shavings), 40 climb out in a very short time, when not treated. R9 Mice remaining in the dish for more than 3 minutes 'C H indicates tranquilization. ED equals the dose of test compound at which 50% of the mice remain in the dish.

Pedestal test: The untreated mouse leaves the pedestal in less than a minute to climb back to the floor R I of the standard mouse box Tranquilized mice will 5 stay on the pedestal for more than one minute.

Nicotine antaqonism test: Mice in a group of 6 are injected with the test compound. Thirty minutes later the mice including control (untreated) mice xx vc are injected with nicotine salicylate (2 mg./kg.). The control mice show overstimulation. i.e., (1) running convulsions, followed by (2) tonic exten wherein R and R are defined as above; R' is hydrofits; fillmwcd by (3) death gen or chloro; R is chloro or fluoro; and the pharma- TESTING FOR ANXIETY ANTAGONISM cologically acceptable acid addition salts thereof. I v

The process for the production of compounds of for- IN I RODUC HON mula XXIV comprises: heatingacompound of formula It is generally accepted that one result of psychic I with the novel reagent XIV to yield compound II; re stress is an increase in plasma corticosteroid levels. acting compound II with sulfuric acid to obtain com- (See Table I). A number of investigators have shown pound Ill, reacting compound III with hydrazine to obthat many psychoactive compounds have an effect on tain compound IV and alkylating compound IV with plasma corticosteroid levels in both the unstressed [V. alkylhalides or formaldehyde, sodium cyanobor- Marc and P. L. Marselli. J. Pharm, Pharmac. II, 785 ohydride and acetic acid, to give V, or alternatively re I969 S. Makela. E. Naatanen and U. K. Rinne. Acta ductively alkylating IV in the presence ofa suitable cat- Endocr. 32: ll I959). R. W. O. Sevy. E. A. Ohler and alyst to give a compound of formula XXIV. Com- A. Weincr, Endocrinology 61: 45 (1957), S. Makela.

E. Naatanen and U. K. Rinne Acta Endocr. 32: l(l959)] and stressed animal [R. W. O. Sevy, E. A. Ohler and A. Weiner. Endocrinology 61: 45 1957) C. W. H. Harvard, V. F. Saldanka, R. Bird, and R. Gardner. J. Endocr. 52: 79 (1972) A. Pekkarinen and M. Haataja. The inhibiting effect of tricyclic antidepressant drugs on the increase of the corticosteroid content by reserpine in the rat plasma..Congress of International Collegiurri of Neuropsychopharmacologium, Copenhagan, Aug. 14-17, 1972. 1. Therefore corticosteroid levels were studies in stressed rats as possible test parameter for psychoactive drugs.

METHODS AND MATERIALS General procedure Male rats weighing 120-140 gm each were arranged five to a cage in the animal room and left that way overnight. Between 8.00 and 9.00 a.m. the following day the rats were injected with the drug intraperitoneally and left in their cages. After one hour the groups of rats were placed into different cages and moved to a room where a radio was playing loudly. Thirty minutes later the rats were given a sham intraperitoneal injection. The animals were anesthetized with halothane minutes later, the heart exposed surgically and 3.S5ml of blood was drawn from the right ventricle into a heparinized Sec plastic syringe using a 20 gauge needle. The blood samples were stored on ice until centrifugation (1000g) within 20 minutes. The plasma was stored at 4C until assayed (within 3 hours).

Assay procedure The corticosteroid levels were determined fluorometrieally using a procedure adapted from that proposed by V. H. T. James et al., British Med. .1. 2, 310 [1971]. Two ml. of plasma is extracted with 15 ml. of methylene chloride by shaking for 10 minutes in a 50 ml. glass stoppered tube on a mechanical shaker. After the phases have been allowed to separate, the plasma layer is aspirated off and discarded. Reagent blanks (2 ml water) and standards (2 ml of 50 pg cortisol/100 ml water) are treated in the same manner. To develop fluorescence, 5 ml, of the methylene chloride extract is added to 3 ml of sulfuric acid: ethanol (7:3) in a lS-ml. glass stoppered tube and shaken vigorously for -30 seconds. The acid layer is trans-- (fluorescence of test )-(fluorescence of blank) The groups of rates were isolated for one hour between injection and stress period.

TABLE 111 Corticosteroid Level in Response to Diazepam (Valium) in Stressed Rats Librium also antagonized increases in corticosteroid levels (at about 0.5 the potency of diazepam). Chlorpromazine (Merck index 8th ed., page 250) and lmipramine (Merck lndex 8th ed., page 562) are practically inactive in this test.

The compound, 8-chlorol [(dimethylamino )methyl ]-6-phenyl- 4H-imida2o[ 1,2- a][ l ,4]benzodiazepine, of this invention is superior to Valium on equal dosages.

The pharmaceutical forms contemplated by this invention include pharmaceutical compositions suited for oral, parenteral, and rectal use, e.g., tablets, powder packets, cachets, dragees, capsules, solutions, suspensions, sterile injectible forms, suppositories, bougies, and the like. Suitable diluents or carriers such as carbohydrates (lactose), proteins, lipids, calcium phosphate, cornstarch, stearic acid, methylcellulose and the like may be used as carriers or for coating purposes. Water and oils, e.g., coconut oil, sesame oil, safflower oil, cottonseed oil, peanut oil may be used for preparing solutions or suspensions of the active drug. Sweetening, coloring, and flavoring agents may be added.

For mammals and birds, food premixes with starch, oatmeal, dried fishmeat, fishmeal, flour and the like can be prepared.

In feed for chicken, swine or cattle from 25-25,000 mg. of compounds of formula XXIV including formulae 1V and V, or acid addition salts thereof are incorporated per ton of feed.

As tranquilizers, the compounds of formula XXIV (including XXlVa and XXlVb) can be used in unit dosages of 0.2 mg.25 mg./kg., preferably between 0.5 and 10 mg./kg, in oral or injectable preparations as described above, to alleviate tension and anxieties in pg corticosteroids] l 00-ml-plasma= ug/lOO ml.

(fluorescence of standard)-(fluorescence of blank) TABLE 1 Change in Corticosteroids Le\ el in Response to Stress Sampled 1 hour after injection TABLE II Corticosteroids Levels and Duration of Stress Length of Stress Period (ortieosteroid Level before Sampling lug/I00 ml) '/2 hr. 98 t 3.5

1 hr. 107 I I15 2 hr. I65 I 5.3

mammals, or birds, such as e.g., occurs when animals are in travel. For larger mammals the lower dosages are indicated. For the treatment of anxiety in mammals, unit dosage forms of l to 30 mg./kg. are indicated. In large mammals 25 kg. and over, 2 to 20 mg. unit dosage is considered satisfactory.

The starting materials of formula I of this invention, substituted or unsubstituted 1,3-dihydro-S-phenyl-Z-H- l.4-benzodiazepineZ-thiones. are described by G. A. Archer and L. H. Sternback [.l. Org. Chem. 29, 231 (1964) and U.S. Pat. No. 3,422,091 These compounds l are made by the reaction of the known substituted or unsubstituted l.3-dihydro-S-phenyl-ZH- l .4- benzodiazepin-Z-ones by heating with phosphorus pentasulfide in pyridine for about 45 minutes. (Archer et al., ibid. The following compounds of formula I are representative starting materials:

7-chlorol ,3-dihydro--( o-chlorophenyl )-2H- I ,4-benzodiazepine-Z-thionc;

7-chlorol ,3-tlihydro-S-phenyl-ZH- l ,4-bcnzodiazcpine-Z-thione;

7fluorol ,3-dihydro-S-phcnyl2H- l ,4-benzodiazepine- Z-thionc; 7-fluro-1,3-dihydro-5-(2,6difluorphenyl)-2H-l,4-benzodiazcpinc-Z-thione;

7-chlorol ,3-dihydro-S-( o-fluorophenyl )-2H- l ,4- benzodiazepineZ-thione;

7-fluorol ,3-dihydro-5-( o-chlorophenyl )-2-H- l ,4-benzodiazepine-Z-thione; 7-chloro-1,3-dihydro-5-(2,6-difluorophenyl)2H-l,4- benzodiazepine-2-thione;

7-trifluoromethyll ,3-dihydro-5-( o-chlorophenyl )-2- H- l ,4-benzodiazepine-Z-thione;

7-trifluoromethyl-l ,3dihydro-5-phenyl-2H- l ,4-benzodiazepi ne-Z-thione;

7-nitrol ,3-dihydro-5-phenyI-ZH- l ,4-bcnzodiazepinc- Z-thione;

7-nitro- I ,3-dihydro-5-( o-chlorophenyl )-2H-l ,4-benzodiazepinc-Z-thione;

8-chlorol ,B-dihydro-S-phenyl-ZH- l ,4benzodiazepine-Z- thione;

9-trifl uoromethyll ,3-dihydro-5-( o-fluorophenyl )-2H- l ,4-benzodiazepine-Z-thione; l ,3-dihydro-5-( o-chlorophenyl )-2H- 1 ,4-benzodiazepine-2-thione; 6-fluoro l ,3-dihydro-5-( o-fluorophenyl )-2-H- l ,4-benzodiazepine-Z-thione; 7-chlorol ,3-dihydro-3-ethyl-5-phenyl-2H- ,4-benzodiazepine-Z-thione; 7-chlorol .3-dihydro-3-methyl-5-( o-chlorophenyl 2H- 1 .4-benzodiazepine-2-thione; 7-nitro-l ,3-dihydro-3-methyl-S-(o-chlorophenyl)-2H- l ,4-bcnzodiazepine-2-thione; 7-chlorol ,3-dihydro-3-methyl-5-( 2,6-difluorophenyl 2H l,4-benzodiazepine-2 thione; 7-bromol ,3-dihydro-3-methyl-5-( o-chlorophenyl ZH-l .4-benzodiazepine-2-thione; 7-trifluoromethyl-l ,3-dihydro-3-methyl-5-(ochlorophenyl )-2H-l ,4-benzodiazepine-Z-thione; and the like.

In carrying out the process of this invention, a starting compound of formula I and a (3- phthalimidoacetonyl)-amine, ethylene ketal is reacted together. In the preferred embodiment of this invention. the reaction is carried out in an organic solvent, inert in this reaction, eg in alkanols, such as methanol, ethanol, lor 2- propanol, n-butanol, tetrahydrofuran, dioxane or the like. Heating the reaction mixture between C and its reflux temperature, as well as maintaining a nitrogen atmosphere, are preferred. The reac tion period id between 6 to 48 hours, with 12 to 24 hours at 50 to 75C preferred. The product ll, 5- phenyl-Zl 3-phthalimidoacetonyl )amino1-3H- l ,4- benzodiazepine, ethylene ketal thus obtained, is recovered and isolated by standard procedures, e.g., filtration (the compound II is not soluble in the cold sol vent), chromatography and/or crystallization from solvent mixtures e.g. methanol/ethyl acetate, acetone, carbon tetrachloride/methanol, or the like.

Compound Il, thus obtained, is treated with excess concentrated sulfuric acid at 2()3()C (room temperature) in a nitrogen atmosphere for 6-24 hours. This reaction mixture is then quenched in cold water, adjusted to pH 8, and the resulting product Ill, a l phthalimidomethyLb-phenyl-4-H-imidazo[ [,2-

a][ l ,4lbenzodiazepine, is recovered by extraction e.g. with chloroform, tetrahydrofuran, methylene chloride or the like. Purification of compound III is carried out by conventional methods.

Compound Ill is then reacted with an excess of hydrazine (L5 to l() mole equivalents of hydrazine per one mole equivalent of compound III) or hydrazine hydrate at temperatures from 2()75, preferably at room temperature (20 to 30C), in ethanol under a nitrogen atmosphere. One to 24 hours reaction time is generally required. After the reaction is completed, the reaction mixture is filtered. The mother liquors containing the amino compound IV are redissolved in an organic solvent and the isolation and purification is made by treatment with mineral acid, generally hydrochloric acid to form the hydrochloride of [V which is further recrystallized to give the pure hydrochloride of IV, I- (aminomethyl )-6-phenyl-4H-imidazo-[ l,2 a][ l,4]benzodiazepine hydrochloride.

Compound IV is alkylated by dissolving the free amine in a suitable solvent, preferably acetonitrile and treating the solution in a nitrogen atmosphere successively with formaldehyde (37% aqueous formalin) in a large excess and then sodium cyanoborohydride [NaBH CN]. The reaction mixture is then adjusted to a pH of 6.4 to 6.8 by addition dropwise of acetic acid dissolved in acetonitrile under continuous stirring. The thus-produced product V is recovered in the crude state by evaporating the reaction mixture in vacuo and is purified by chromatography, and/or recrystallization.

The monomethylated compound may be obtained by refluxing compound V with phenyl chloroformate and potassium or sodium bicarbonate in a suitable organic solvent, followed by refluxing with an alkali metal hydroxide.

Alternatively compounds of the formula XXIV may be obtained by treating IV with an aldehyde or ketone of from two to three carbon atoms followed by catalytic reduction of the resulting Schiff base in a suitable organic solvent.

Variations of these reactions can be made and the resulting products can then be converted by the processes shown above, to give the corresponding final compounds as illustrated by formula XXIV. These processes will subsequently be shown in examples. In the same manner the various reactants used for these reactions will be shown in the subsequent examples.

The following examples are illustrative of the processes and products of the present invention, but are not to be construed as limiting:

EXAMPLE I Phthalimidoacetone ethylene ketal A solution of phthalimidoacetone 6l .9 g (300 mmole) and ethylene glycol l8.9 g 300 mmole) in 300 ml of benzene in the presence of concentrated sulfuric acid 1 drop) is refluxed with stirring for 24 hours. An additional portion of ethylene glycol l8.9 g., 300 mmole) and p-toluenesulfonic acid 3 mg) is added and refluxing is continued for 65 hours. The reaction mixture is cooled in ice, washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The benzene is removed in vacuo and the residue is crystallized from methanol to give 67 g of phthalimidoacetone, ethylene ketal as white prisms of melting point )2-94"C.

A solution of phthalimidoacetone ethylene ketal (2.47 g, l mmole) in l0 ml of diethylene glycol is heated on a steambath. To this hot solution bromine (l.6 g, mmole) is added dropwise under nitrogen. The reaction mixture is cooled to room temperature and is quenched -in ml hexane. To this mixture is added solid sodium carbonate followed by chloroform and ice water. The organic layer is separated and the aqueous layer is extracted 3 times with chloroform. The chloroform extracts are washed with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue is crystallized from ethyl acetate/- hexane to afford 2 g (55%) of (3- phthalimidoacetonyl)bromide, ethylene ketal as white prisms of melting point l39- l 4 l C. An analytical sample has a melting point of l40l4l C.

Anal. Calcd, for C H BrNQ, C, 47.87; H, 3.7l; N, 4.29; Br, 24.50; Found: C. 47.66, H 3.60; N, 4.42; Br, 24.76

Example 3 (3-Phthalimidoacetonyl)azide, ethylene ketal A suspension of (3-phthalimidoacetonyl)bromide, ethylene ketal (70.0 g, 210 mmole) and sodium azide (33.0 g, 504 mmole) in ml. of dimethyl sulfoxide is heated on a steambath under nitrogen for 4 days. The above mixture is poured onto ice and extracted with chloroform (BX, 500 ml). The chloroform extract is washed with water (2X), saturated sodium chloride solution and dried over anhydrous sodium sulfate. Evaporation of chloroform in vacuo gives a white oil which on trituration with hexane crystallizes to afford 59 g, (95%) of 3-phthalimidoacetonyl )azide, ethylene ketal as white prisms of melting point 90.592C. An analytical sample recrystallized from ethyl acetate hexane has a melting point 92.593.5C.

Anal, Calcd, for C H N O mw 288.272C, 54.16; H, 4.20; N, 19.44; Found: C, 53.95; H, 4.23; N, 19.15

Example 4 (3-Phthalimidoacetonyl )amine, ethylene ketal A solution of l 1.52 g (40.0 mmole) of (3- phthalimidoacetonyl)azide, ethylene ketal in 250 ml of ethyl acetate is hydrogenated over 1 g of l()% palladium on charcoal at room temperature, and 50 psi for 2.5 hours. The above mixture is filtered, washed thoroughly with more ethyl acetate and evaporated in vacuo to afford 10 g (96% of 3- (phthalimidoacetonyl)amine ethylene ketal as a white oil. This compound is used directly for the next step.

Example 5 (3-Phthalimidoacetonyl )dimethylamine, ethylene ketal To a solution of 3-phthalimidoacetonyl )amine, ethylene ketal (5.2 g, 20 mmole) and 37% formalin solution (6.4 g, 80 mmole) in 250 ml of methanol/ethylacetate (200:50 ml) mixture, is added [0% palladium on charcoal (5 g) as a catalyst. The resulting mixture is hydrogenated at room temperature under 50 psi pressure for l8 hours. The catalyst is filtered off, washed thoroughl y with more methanol, and the methanol is evaporated in vacuo, to afford S g (86%) of white oil, which 14 crystallizes to afford (3-phthalimidoacetonyl)- dimethylamine, ethylene ketal of melting point l23l25C.

Anal. Caled, for C H N O mw 290.3l1C, 62.05; H, 6.25; N, 9.65; Found: C. 6l.62; H, 6.45; N, 954.

Example 6 l-Phthalimidobutanone To a stirred suspension of potassium phthalimide (5.0 g, 0.027 mmole) in 25 ml of dimethylformamide is added, dropwise, 3.80 g (0.025 mmole) of lbromobutanone. The mixture is heated for l0 hours at C under in nitrogen and then ml of chloroform is added. The resulting mixture is poured into 30 ml of water and the organic layer is separated and washed with l0 ml of ().2N sodium hydroxide. The resulting chloroform and dimethylformamide solution is dried over anhydrous sodium sulfate, and evaporated in vacuo to give l-phthalimidobutanone.

Example 7 l-Phthalimidobutanone, ethylene ketal In the manner given in Example I, lphthalimidobutanone is refluxed with ethylene glycol and a catalytic amount of p-toluenesulfonic acid in benzene to give l-phthalimidobutanone, ethylene ketal.

Example 8 l-Phthalimid0-3-bromo-2-butanone, ethylene ketal In the manner given in example 2, lphthalimidobutanone, ethylene ketal in diethylene glycol is heated with bromine to give l-phthalimido-B- bromo-2-butanone, ethylene ketal.

Example 9 l-Phthalimido-3-azido-2-butanone, ethylene ketal In the manner given in example 3, l-phthalimido-3- I bromo-Z-butanone ethylene ketal in dimethyl sulfoxide is heated with sodium azide to give l-phthalimido-3- azido-Z-butanone, ethylene ketal.

Example 10 l-Phthalimido-3-amino-2-butanone, ethylene ketal In the manner given in example 4, l-phthaIimido-3- azido-Z-butanone, ethylene ketal in ethyl acetate is reduced with molecular hydrogen and palladium on charcoal to give l-phthalimido-3-amino-2 butanone, ethylene ketal.

Example 1 l l-Phthalimido-3-( dimethylamino)-2-butanone ethylene ketal In the manner given on example 5, l-phthalimido-3- amino-2-butanone ethylene ketal and an aqueous 37% formalin solution in methanol/ethyl acetate mixture is reductively methylated with molecular hydrogen and palladium on charcoal to give l-phthalimido-3-(dimethylamino)-2-butanone, ethylene ketal.

Example 12 7-Chloro-5-phenyl-2-[ 3-phthalimidoacetonyl amino] -3H-l,4-henzodiazepine, ethylene ketal A suspension of 7ehloro-l.3-dihydro-5-phenyl-2H- l,4-benzodiazepine-2-thione (L44 g; 5 mmole) and (S-phthalimidoacetonyl)amine, ethylene ketal, (4.5 g. 17 mmole) in 40 ml of absolute ethanol is heated at 60 C. overnight under nitrogen. The above solution on cooling gives 750 mg of a white solid of melting point 22(l229 C which is discarded. The filtrate l is concentratcd in vacuo and the residue is chromatographed on a silica gel column using 371 methanol-97% chloroform to afford 950 mg. of 7-ehloro-5-phenyl-2-[(3- phthalimidoaeetonyl)amino]-3H-1.4-benzodiazepine. ethylene ketal. An analytical sample recrystallized from acetone, has a melting point of l42l45C.

Anal. Calcd. for H- N 0 C, 65.30; H, 4.50; N, I085; Cl, 6.88: Found: C, 65.10; H, 4.55; N. K185; Cl. 6.79.

Example l3 7-Chloro-5-(o-chlorophenyl )-2-[ 3- phthalimidoacetonyl )amino ]-3H- l ,4-benzodiazcpine, ethylene ketal A suspension of 7-chlorol ,3-dihydro--(ochlorophenyl)-2H-l,4-benzodiazepine-2-thione (l8 g 56 mmole) and (3-phthalimidoacetonyl)amine, ethylene ketal (28.88 g, l l2mmole) in 800 ml. of absolute ethanol is heated on a steambath, under nitrogen for 24 hours. The above mixture is then evaporated to dryness in vacuo to give 27 g (8471) of 7-chloro-5-(ochlorophenyl)-2-[(3-phthalimidoacetonyl )amino1-3H- 1,4-benzodiazepine, ethylene ketal as a buff-colored compound of melting point l80l90C. An analytical sample recrystallized from methanol ethyl acetate has a melting point of ()202 C.

Anal. Calcd. for C H Cl N O C, 61.21; H, 4.04; N. H120; Cl. 12.90; Found: C, 6l.42; H. 4.1 l; N, 9.93; Cl. I257.

Example 14 7-Chloro-5-( o-chlor0phenyl )-2- 3-phthalimidol-methylacetonyl )amino]-3Hl .4-benzodiazepine, ethylene ketal In the manner given in example 12 a suspension of -ehlorol ,3-dihydro-5-(o-chlorophenyl )-2H l ,4- benzodiazepine-2-thione (9 g. 28 mmole) and l-phthalimido-3-amino-2-butanone ethylene ketal l5.4 g. 56.0 mmole) in 400 ml. of absolute ethanol is heated on a steambath under nitrogen for 24 hours. After the usual work-up and isolation procedure. one obtains 7-chloro5-(o-chlorophenyl )-2- 3-phthalimidol -methylacetonyl )amino ]-3H- 1 .4- benzodiazepine ethylene ketal.

Example [5 give 16 Example 16 7-Nitro-Sphenyl-2-[ 3-phthalimidoacetonyl amino l-3 H-l ,4-benzodiazepine, ethylene ketal In the manner given in Example l2, 7-nitro-l,3- dihydro-S-phenyl-ZH-l ,4-benzodiazepine-2-thione is heated with (3-phthalimidoacetonyl)amine, ethylene ketal in ethanol to give 7-nitro-S-phenyl-2-[(3- phthalimidoaeetonyl )amino ]-3H- l .4-benzodiazepine ethylene ketal.

Example 17 7-Nitro-S-(o-chlorophcnyl )-2-[( 3- phthalimidoaeetonyl)amin0]-3H-1.4-benzodiazepine, ethylene ketal In the manner given in example 12, 7-nitro-l,3- dihydro-5-( ochlorophenyl )-2H- 1 ,4-benzodiazepine-2- thione is heated with (3-phthalimidoacetonyl)amine, ethylene ketal in ethanol to give 7-nitro-5-(ochlorophenyl )-2- 3-phthalimid0acetonyl )amino]3H- l ,4- benzodiazepine, ethylene ketal.

Example I 8 7-Trifluoromethyl-S-phenyl-2-[( 3- phthalimidoacetonyl )aminol-3H- l ,4-bcnzodiazepine, ethylene ketal In the manner given in example l2, S-trifluormethyl- LS-dihydro-S-phenyl-Zl-ll ,4-benzodiazepine-2-thione is heated with (3-phthalimidoacetonyl )amine, ethylene ketal in ethanol to give 7-trifluoromethyl-S-phenyl-2- phthalimidoaeetonyl )amino]-3H- l .4-henzodiazepine, ethylene ketal.

Example 19 7'Trifluor0methyl-5 o-chlorophenyl )-2-[ 3- phthalimidoacetonyl )amino ]-3 H- l ,4-benzodiazepine, ethylene ketal In the manner given in example 12, 7- trifluoromethyl-( o-chlorophenyl )-2H- l ,4-benzodiazepine-2-thione is heated with (3- phthalimidoacetonyl)amine, ethylene ketal in ethanol to give 7-trifluoromethyl-5-(o-chlorophenyl )-2- [(3-phthalimidoacetonyl)amino1-3H-l.4- henzodiazepine, ethylene ketal.

In the manner given in Example 12, other compounds of formula ll can be produced. such as: 7-nitro-5-( 2,6-difluorophenyl )-2-[( 3- phthalimidoacetonyl)-amino]-3H-1.4-henzodiazepine, ethylene ketal;

7-H uoro-5-( 2,6-difluorophenyl )-2-[( 3- phthalimidoaeetonyl )-amino ]-3H-l ,4-benzodiazepine, ethylene ketal; 7-fluoro-5-phenyl-2-[( 3- phthalimidoacetonyl )amino ]3l-ll .4-henzodia2epine. ethylene ketal;

7-tluoro-5-( o-chlorophenyl )-2-l 3- phthalimidoacetonyl)-amino]-3H-1.4-benzodiazepine. ethylene ketal;

7-fluoro-5-( o-fluorophenyl )-2-{( 3- phthalimidoacetonyl )-amino]3H- l ,4-benzodiazepine. ethylene ketal:

o-chloro-5-phenyl-2-[ 3-phthalimidoaeetonyl )amino]- 3H l.4-henzodialepinc ethylene ketal; X-bromo-5-(ochlorophenyl )-2-[( 3-phthalimidoaeetonyl amino]-3H-l ,4-ben20diazepine, ethylene ketal;

5-( o-chlorophenyl )-2-[( 3- phthalimidoacetonyl)aminol-3H-1,4-benzodiazepine, ethylene ketal;

7-trifluoromethyl-5-( 2,6-difluorophenyl )-2-[( 3- phthalimidoacetonyl)amino]-3H-1,4-benzodiazepine, ethylene ketal;

7-trifluoromethyl-5-( o-fl uorophenyl )-2-[ 3- phthalimidoaeeto'nyl)aminol-BH-1,4-benzodiazepine, ethylene ketal; and the like.

Example 20 8-Chloro-1-(phthalimidomethyl)-6-phenyl-4H- imidazo[ 1,2-a][ 1,4]benzodiazepine A suspension of 7-chloro-5-phenyl-2-[ 3- phthalimidoacetonyl)amino]-3H-1,4-bcnzodiazepine, ethylene ketal g, 29 mmole) in 50 ml. of concentrated sulfuric acid is stirred at room temperature under nitrogen for 18 hours. This is then quenched in cold water, neutralized with l()'7r aqueous sodium hydroxide, and extracted with chloroform (400 ml, 4X). The chloroform solution is washed with water, saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to afford a yellow oil. This is crystallized from ethyl acetate/hexane to afford 5.6 g (42.5%) of 8- chloro- 1- (phthalimidomethyl )-6-phenyl-4H- imida2o[1,2a][l,4]benzodiazepine of melting point 236-240C. An analytical sample recrystallized from ethyl acetate/hexane has a melting point of 240242C.

Anal. Calcd. for C ,,H CIN O C, 68.95; H, 3.78; N, 12.37; Cl, 7.83; Found: C, 68.87; H, 4.22; N, 12.35; Cl, 7.63.

Example 21 8-Ch1orol -(phthalimidomethyl )-6-(o-chlorophenyl 4H-imidazo[ 1,2-a][ 1,4]benzodiazepine A suspension of 7-chloro-5-(o-ehlorophenyl)-2-[(3- phthalimidoacetonyl )aminol-BH- l ,4-benzodiazepine, ethylene ketal (800 mg, 1.5 mmole) is stirred in 3ml. of concentrated sulfuric acid at room temperature under nitrogen for hours. The above mixture is quenched in ice-water, neutralized with 5% aqueous sodium hydroxide, and extracted with chloroform (50 ml, 3X). The chloroform extract is washed with water, saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo leaving a white oil. This is crystallized from ethyl acetate/hexane to give 430 mg. (617z) 8-chlorol-( phthalimidomethyl )-6-( o-chlorophenyl )-4H- imidazo[ l,2-a]-[ 1,4]benzodiazepine. An analytical sample recrystallized from ethyl acetate/hexane has a melting point of 218-220C Anal. calcd for C ,,H ,,Cl. .N,O mw 487.33: C, 64.08; H, 3.31; N, 1 1.50; C1, 14.35 Found: C, 63.90; H, 3.35; N, 1126; C1, 14.06.

Example 22 8-Chlorol phthalimidomethyl )2-methyl-6 (ti-chlorophenyl )-4H-imidazo[ l,2- a H l ,4 ]henzodiazepine In the manner given in example 20 a suspension of 7-ch1oro-5-fo-chlorophenyl )-2-[(3-phthalimidolmethylacetonyl )amino1-3H-l ,4-benzodiazepine, ethylene ketal in concentrated sulfuric acid is stirred at room temperature under nitrogen for 18 hours and the reaction mixture poured onto ice, treated with base and the product isolated to give 8-chloro- 1 (phthalimidomethyl )-2-methyl-6-( o-chlorophcnyl 4H-imidazo[ l,2-a]l l ,4lbenzodiazepine.

Example 23 8-Nitro-1-(phthalimidomethyl)-6-phenyl-4H- imidazol l,2-][ 1,4]benzodiazepine In the manner given in Example 20, 7-nitro-5-phenyl- 2-[( 3-phthalimidoaeetonyl )aminoj-3 H- l ,4- benzodiazepine. ethylene ketal is treated with concentrated sulfuric acid, then quenched to give, after neutralization, 8- nitro-l-(phthalimidomethyl)-6-phenyl- 4H-imidazo[ l,2-a][ 1,4]benzodiazepine.

Example 24 B-Nitrol phthalimidomethyl )-6-(o-chlorophcnyl 4H-imidaz0[ l,2-a 1,4]henzodiazepine In the manner given in Example 20, 7-nitro-5-(ochlorophenyl )-2-[(3-phthalimidoacetonyl )amino1-3H- 1,4-benzodiazepine, ethylene ketal is treated with concentrated sulfuric acid, then quenched to give, after neutralization, 8-nitrol phthalimidomethyl )6-( ochlorophenyl )-4H- imidazo[ l ,2-a][ 1,4]benzodiazepine.

Example 25 S-Trifluoromethyll-(phthalimidomethyl1-6- phenyl-4H-imidazo[ 1,2- 1,4]henzodiazepine In the manner 20, trifluoromethyl- 5-phenyl-2-[( 3-phthalimidoacetonyl )amino1-3H- l ,4- benzodiazepine, ethylene ketal is treated with concentrated sulfuric acid, then quenched to give, after neutralization, S-trifluoromethyll-( phthalimidomethyl 6-phenyl-4H-imidazo-[l ,2-a] [l ,4]benzodiazepine.

given in Example 7- Example 26 B-Trifluoromethyll -phthalimdomethyl )-6- (o-chlorophenyl )-4H-imidazo[ 1,2- a ll 1,4]henzodiazepine in the manner given in example 20, 7- trifluoromethyl-5-( o-chlorophenyl )-2-[( 3- phthalimidoacetonyl )amino ]-3 H- l ,4-henzodiazepine, ethylene ketal is treated with concentrated sulfuric acid, then quenched to give, after neutralization, 8- trifluoromethyll phthalimidomethyl o-(o-chlorophenyl )-4H-imidazo[ 1,2a-

][ 1,4 lbenzodiazepine.

Example 27 II-(a-phenyL4H-imidazol l.2-al[ l.4 ]hcnzodiazcpines can be synthesized. Representative compounds, thus obtained. include:

8-fl uoro-( l-phthalimidomethyl )-6-( 2,6- difluorophenyl 4H-imidazol I ,2- l.4 ]henzodiazepine;

8fluorol phthalimidomethyl )-6'phenyI-4H- imidazol l .2a]-[ l.4]henzodiazepine'.

8-fluoro- I phthalimidomethyl )-6-( o-chlorophenyl 4H-imidazo[ l.2-a][ l.4 ]benzodiazepine;

8-fluoro- I phthalimidomethyl )-6-(o-fluorophenyl 4H-imidazo[ l,2-a 1,4 ]benzodiazepine;

7-chlorol phthalimidomethyl )-6-phenyl-4H- imidazo[ l.2-a]-[ I .4]benzodiazepine;

S-hromol phthalimidomethyl )-6-( o-chlorophenyl 4H-imidazo[ I .2-a][ l .4]benzodiazepine;

l-( phthalimidomethyl )-6-( o-chlorophenyl )-4H- imidazo-[ l .2-a 1.4 lbenzodiazepine; S-trifluoromethyll (phthalimidomethyl )-6-( 2,6- difluorophenyl )-4H-imidazo[ I ,2-a][ 1,4]benzodiazepine; S-trifluoromethyl- I phthalimidomethyl )-6-(ofluorophenyl )-4H-imidazo[ l ,2-a][ 1,4]benzodiazepine; and the like.

Example 28 S-Chloro- I aminomethyl )-6-phenyl-4H-imidazol ,2-a][ I ,4]benzodiazepine dihydroehloride A suspension of 8-chloro-l-(phthalimidomethyI)-6- phenyl-4H-imida2o[l.2-a][1.4]benzodiazepine (I g, 2 mmole) and hydrazine hydrate (500 mg, 10 mmole) in ml. of absolute ethanol is stirred at room temperature under nitrogen for 18 hours. The white solid (byproduce I) which separated is removed by filtration. The filtrate from above is evaporated to dryness and the residue is dissolved in chloroform. The chloroform solution is washed with water. saturated sodium chloride solution, dried over anhydrous sodium sulfate. and concentrated in vacuo. to give a white oil. This oil is dissolved in ethyl acetate and to this is added methanolic hydrogen chloride. The resulting solution is concentrated to a small volume and cooled, to afford 830 mg. (95%) of S-chlorol -(aminon1ethyl )-6-phenyl- 4H-imidazo[ l .2-a][ l,4]benzodiazepine dihydrochloride. An analytical sample is recrystallized from methanol ethyl acetate and has a melting point of 275-280 C.

Anal. Caled. for C, H ,-,CIN .2HCI.V2 H O: C. 53.42; H, 4.48; N. l3.85; Cl. 26.27 Found: C. 53.53; H, 4.34; N. [4.05; CI, 26.I7.

Example 29 8-Chlorol aminomethyl )-6-( ochlorophenyl )4H-imidazo[ 1,2-a][ I ,4]benzodiazepine A suspension of 8-chloro-I-(phthalimidomethyl)-6- (o-chlorophenyl )-4H-imidazo[ 1.2- a][ I .4lhenzodiazepine (214g, 4.4 mmole) and hydrazine hydrate l g, 22 mmole) in 75 ml. of absolute ethanol is stirred at room temperature under nitrogen for 20 hours. The white solid which precipitates is removed by filtration. The ethanol solution is evaporated to dryness in vacuo and the residue is dissolved in chloroform. The chloroform solution is washed with water. then with saturated sodium chloride solution, dried over anhydrous sodium sulfate. and evaporated in vacuo to give 1.56 g [(Xl'lr of yellow oil. This oil is alkylated without any purification [example 37].

Example 30 B-Chloro- I aminomethyl l-2-methyl-6-(ochlorophenyl )-4H-imidazo[ l .2-a}[ l .4]benzodiazepine In the manner given in Example 28, a suspension of 1.00 mmole of 8-chloro-I-(phthaIimido)methyl-2- methyl-6-(o-ehlorophenyD-4H-imidazo[l .2- aj[ l,4]benzodiazepine is treated with 5.00 mmole of hydrazine hydrate in 12 ml. of absolute ethanol at room temperature for l8 hours to afford. after removal of the phthalazine by-product, S-ehloro-I-aminomethyl-2- methyl-6-(o-chlorophenyIJ-4H- imidazol l.2-a][ l.4]benzodiazepine.

Example 3 1 S-Nitro- I aminomethyl )-6-phenyl-4H-imidazol,2-a][ l ,4]benzodiazepine In the manner given in Example 28, 8-nitro- I (phthalimidomethyl )-6-phenyl-4H-imidazo[ l ,2- a][ l ,41-benzodiazepine is reacted at room temperature with hydrazine hydrate, dissolved in ethanol to give 8- nitro-l-(aminomethyl)-6-phenyl-4H-imidazo[I ,2- a][ l,4]benzodiazepine.

Example 32 S-Nitrol aminomethyl )-6-( o-chlorophenyl 4H-imidazo[ l ,2-a][ I.4]benzodiazepine In the manner given in Example 28, 8-nitro-I- (phthalimidomethyl )-6-( o-chlorophenyl )-4H- imidazol I .2-a]-[ I ,4lbenzodiazepine is reacted at room temperature with hydrazine hydrate, dissolved in ethanol to give S-nitro- I -(aminomethyl)-6-(o-chlorophenyl- 4H-imidazo[l ,2-a][1,4l-benzodiazepine.

Example 33 8-Trifl uoromethyll aminomethyl )-6-phenyl- 4H-imidazo[ l ,2-a][ l.4]benzodiazepine In the manner trifluoromethl phthalimidomethyl )-6-phenyl-4Himidazo[ l ,2-a]- [l.4]benzodiazepine is reacted at room temperature with hydrazine hydrate. dissolved in ethanol, to give -trifluoromethyll-( aminomethyl )-6-phenyl-4H- irnidazo[ l .2-a]-[ l.4 lbenzodiazepine.

given in Example 28, 8-

Example 34 given in Example 8- Example 35 8-Chlorol-( aminomethyl )-o-( 2.6-difluorophenyl 4H-imidazo[ 1,241 II I .4lhenzodiazepine 1n the manner given in Example 28, 8-chlorol- (phthalimidomethyl )-6-( 2.6-difluorophenyl )-4H- imidazo[l,2-][1,4]benzodiazepine is reacted at room temperature with hydrazine hydrate, dissovled in etha nol, to give 8-chlorol-( aminomethyl )-6-( 2,6 difluorophenyl-4H-imidazol,2'a[ 1.4]benzodiazepine.

1n the manner given in Example 28. other 1- (aminomethyl )-6-phenyl-4H-imidazo[l ,Z-a] [1 ,4lbenzodiazepines can be prepared. Representative compounds include: 8-fluorol aminomethyi )-6-( 2,6-difluorophenyl )-4H- imidazo-[ 1,2-a][ 1,4]benzodia2epine; X-fluoro- 1-( aminomethyl )-6-o-chlorophenyl-4H- imidazo[ l,2-a][ l ,4]-benzodiazepine; 8flu0ro-1-(aminomethyl)-6-(o-chlorophenyl)-4H- imidazo-[ 1,2-a][ 1,4]benzodiazepine; 8-fluoro- 1 aminomethyl )-6-( o-fluorophenyl )-4H- imidazo-[ 1,2a][ 1,4]benzodiazepine; 7-chloro- 1 -(aminomethyl )-6-( o-chlorophenyl )-4H- imidazo-[ l,2-a][ 1,4]benzodiazepine; 8-bromol aminomethyl )-6-( o-chlorophenyl )-4H- imidazo-[ l ,2-a][ 1,4]benzodiazepine; l-( aminomethyl )-6-( o-chlorophenyl )-4H-imidazo[ 1,2- a]-[ 1,4]benzodiazepine; 8-trifluoromethyl l-( aminomethyl )-6-( 2,6- difluorophenyl 4H-imidazo[ 1,2-a][ 1 ,4]benzodiazepine; 8-trifluoromethyl-1-(aminomethyl)-6-(ofluorophenyl )-4H-imidazo[ 1,2-a][ 1,4]benzodiazepine; and the like.

Example 36 8-Chloro-1-[(dimethylamino)methyl]-6-phenyl-4H- imidazo[ l,2-a][ 1,4]benzodiazepine A stirred solution of 8-chloro-l-(aminomethyl )-6- phenyl-4Himidazo[ 1,2-a][ 1,4]benzodiazepine 1.42 g, 4.3 mmole) in ml. of acetonitrile, under nitrogen, is treated successively with 37% aqueous formaldehyde (2.2 ml) and sodium cyanoborohydride (NaBH CN) (550 mg). This mixture is treated dropwise, with a solution of 0.2 ml. of acetic acid in 2 ml. of acetonitrile over a period of 1 hour and minutes. [The addition is continued until the pH of the reaction mixture is between 6.4 6.81. The mixture is stirred for 15 minutes at ambient temperature and concentrated in vacuo. The residue is treated with cold water saturated with sodium chloride and extracted with chloroform (5- ml., 3X). The chloroform solution is washed with water and saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated in vacuo to give a yellow oil. This oil is chromatographed over silica gel by eluting with 271 methanol-98 71 chloroform mixtures to afford 700 mg. (47%) of 8-chloro-l- [(dimethylamino )methyl ]-6-phenyl-4H-imidazo- 11,2 41,4]benzodiazepine. An analytical sample recrystallizes from ethyl acetate/hexane has a melting point of 181-l82C.

Anal. Calcd. for C H ClNp C, 68.46; H, 5.46; N, 15.97; Cl, 10.10; Found: C6850; H, 5.50; N, 15.92; Cl. 10.37.

Example 37 8-chloro-1-[(dimethylamino)methyl]6-(ochlorophenyl )4H-imidazo[ l ,2-a][ 1,4]benzodiazepine, dihydrobromide and monohydrobromide A stirred solution of 8-chloro-l-(aminomethyl)-6- (o-chlorophenyl )-4H-imidazol 1 ,2-

a][ 1,4]benzodiazepine (4.70 g, 12.9 mmole) in 60 ml. of dry acetonitrile, under nitrogen, is treated successively with 37% aqueous formaldehyde (66ml) and sodium cyanoborohydride 1.65 g). This mixture is treated dropwise, over a period of 1 hour and 30 minutes. with a solution of acetic acid (0.6 ml) in acetonitrile (6ml) and kept at ambient temperature for 15 minutes at which time the mixture is concentrated in vacuo. The residue is mixed with ml of methanol and 2571 aqueous ethylene diamine (60 ml) and refluxed for 45 minutes. The mixture is then diluted with cold water, saturated with sodium chloride and extracted with chloroform ml, 4 times). The chloroform solution is first washed with water, followed by a saturated salt solution, then dried over anhydrous sodium sulfate, and finally, evaporated in vacuo to give 55 g (crude) oil. A portion of this oil is crystallized from methanol/ether mixtures as a monohydrobromide derivative 0f8-chloro-l -[(dimethylamino)-meth y- -6-(o-chlorophenyl)-4H-imida2o[ 1,2-all 1,4]- benzodiazepine (methanol solvate) of melting point 168l71C.

Anal. calcd for C- H ClbhHBr .H O./CH;,OH: C, 49.21; H, 4.63; N, 11.20; Halogen, 30.14 Found: C, 48.94; H, 4.62; N, 11.16; Halogen, 29.84.

A second compound, the dibromide, obtained after chromatography of the free base and reconversion to an HBr derivative (B) has a melting point 19920l C.

Anal calcd for C ,,H,,,CI N .1 /zHBr: C, 47.41; H, 3.88; N, 11.06; Found: C, 47.51; H, 3.98; N, 11.31.

Example 38 8-Chloro-6-( o-chlorophenyl l [(dimethylamino methyl]-2-methyl-4Himidazo{ 1,2-a 11 1,4 ]benzodiazepine. monohydrobromide 1n the manner given in example 36, a stirred solution of 1.0 mmole of 8-chloro-l-aminomethyl-2-methyl-6- (ochlorophenyl )4H-imidazo[ l,2-a][1,4]benzodiazepine in 5.0 ml. of acetonetrile under nitrogen is treated successively with 0.5 ml. of a 37% aqueous formalin solution, and sodium cyanoborohydride 100 mg]. The mixture is treated dropwise with a solution of 0.05 ml. of acetic acid in 0.5 ml. of acetonetrile over a 30 minute period (until the pH is between 6.4 6.8). Following the procedure of example 36, the reaction mixture is worked up. The product is isolated as an oil which crystallizes as a monohydrobromide derivative from methanol/ethyl acetate mixture to afford 8-chloro-6- (o-ch10ropheny)- I -[(dimethylamino)methyll-2 methyl-4H-imidazo[l,2-a][1,4lbenzodiazepine, monohydrobromide. The analytical sample has melting point I94I97C.

Example 39 8-Nitr0-l-{(dimethylamino)methyll-6-phenyl- 4H-imidazol l,2-a][ 1,4] benzodiazepine 1n the manner given in Example 36, B-nitro-laminomethyl )-6-phenyl-4H-imidazo[ 1,2-

a][ l,4}benzdiazepine in acetonitrile, is treated with formaldehyde. then with sodium cyanohorohydride and finally dropwise with acetic acid in acetonitrile to give S-nitrol-[ dimethylamino)-methyl ]-6-phenyl- 4H-imidazo[ l.2a][ l ,4 lhenzodiazepine.

Example 40 8-Nitrol dimethylamino )methyl 1-6-(0- chlorephenyl)-4Himidazo[l ,Z-alll ,4lbenzodiazepine In the manner given in Example 36, 8-nitro-l- (aminomethyl) -6-(o-chlorophenyl)-4H-imidazo[ l ,2- a][ l,4]benzodiazepine, in acetonitrile, is treated with formaldehyde. then with sodium cyanoborohydride and finally dropwise with acetic acid in acetonitrile to give S-nitro-1-[(dimethylamin0)-methy-6-(o-chlorophenyl)-4H-imidaz0[l .Z-a] [1,4l-benzodiazepine.

Example 41 8-trifluoromethyll dimethylamino )methyl]-6- phenyl-4H-imidazo[ l,2-a][ l,4]benzodiazepine In the manner given in Example 36, trifluoromethyll aminomethyl )-6-phenyl-4H- imidazoll,2-a][l,4]benzodiazepine in acetonitrile, is treated with formaldehyde. then with sodium cyanoborohydride and finally dropwise with acetic acid in acetonitrile to give 8-trifluoromethyll [(dimethylamino )methyl ]-6-phenyl-4H-imidazo[ 1.2- all 1.4 ]-benzodiazepine.

Example 42 ti-Trifluoromethyll -[(dimethylamino )methyll-o-(ochlorophenyl )-4H-imida2o[ l ,2-a][ 1,4 ]benzodiazepine In the manner given in 36, 8- trifluoromethyll aminomethyl )-6-( o-chlorophenyl )-4H-imidazo[ 1,2- a][ l.4]-hen2odiazepine, in acetonitrile, is treated with formaldehyde then with sodium cyanohorohydride. and finally dropwise with acetic acid in acetonitrile to give S-trifluorometh-l-[(dimethylamino)methyl]-6- (o-chlor0phenyl)-4H-imidazo[l ,2a][l ,4]benzodiazepine.

Example Example 43 8Chloroldimethylamino )methyl ]-6-( 2.6- difluorophenyl 4H-imidazol l .2- a l ,41henzodiazepine S-fluorol dimethylamino )methyl -6-phenyl4H- imidazo-[ l .2a][ l.4]henzodiazepine; S-fluorol (dimethylamino)methyl1-640- chlorophenyl 4H-imidazo[ l ,2- a][ l ,4]benzodiazepine; B-fluoro-l-[(dimethylaminoJmethyl1-64)- fluorophenyl )-4H-imidazo[ l.2-a][ l ,4 lbenzodiazepine; 7-chlorol -[(dimethlamino)methyl ]-6-( oehlorophenyl )-4H-imidazo[ [,2- a]{ 1,4]benzodiazepine; S-bromo-l-[(dimethylamino)methyl1-6-(0- chlorophenyl )-4H-imidazo[ 1,2- all 1,4]henzodiazepine; l-[ dimethylamino )methyl l-6-( o-chloropheuyl )-4H- imidazo-[ l ,2-a][ 1,4]benzodiazepine; S-trifluoromethyll -[(dimethylamino )methyl ]-6-( 2.6- difluorophenyl )-4H-imidazo[ 1 ,2- a][ 1,4]benzodiazepine; S-trifluoromethyll -{(dimethylamino )methyl }-6-( ofluorophenyl )-4H-imidazo[ l ,2-a][ 1,4]benzodiazepine; and the like.

Example 44 8-Chlorol diethylamino )methyl ]-6-phenyl-4H -imidazo] l ,2-a][ l,4]benzodiazepine A stirred solution of B-chloro-l-(aminomethyll-fiphenyl-4H-imidazo[ l,2-a][ l,4]henzodiazepine 1.42 g, 4.3 mmole) in 20 ml. of acetonitrile under nitrogen is treated successively with acetaldehyde 1.5 ml) and sodium cyanohorohydride (NaBH;,CN) (550 mg). This mixture is treated dropwise, with a solution of (1.2 ml of acetic acid in 2 ml. of acetonitrile over a period of l hour and 30 minutes. [The addition is continued until the pH of the reaction mixture is between 6.4 6.8]. The mixture is stirred for minutes at ambient temperature with concentrated in vacuo. The residue is treated with cold water saturated with sodium chloride and extracted with chloroform (5- ml.. 3X). The chloroform solution is washed with water and saturated sodium chloride solution. then dried over anhydrous sodium sulfate. and concentrated in vacuo to give a yellow oil. This oil is chromatographcd over silica gel by eluting with 2% methanol-989? chloroform mixtures to afford 8-chlorol -i diethylamino )methyl 1 -6-phenyl- 4H-imidazol l.2-a][ lAlhenzodiazepine.

Example 45 8-Chloro-l-[ (dipropylamino)methyl]-6-phenyl-4H -imidazo] l .Z-a][ 1,4]henzodiazepine A stirred solution of B-ehloro-l-(aminomethyl )-(1- phenyl-4H-imidazo[ LZ-ali l .4 lhenzodiazepine 1.42 g, 4.3 mmole) in ml. of acetonitrile under nitrogen, is treated successively with propionaldehyde 194 ml) and sodium cyanohorohydride (NaBH CN) (550 mg). This mixture is treated dropwise. with a solution of ()2 ml of acetic acid in 2 ml. of acetonitrile over a period of 1 hour and minutes. [The addition is continued until the pH of the reaction mixture is between 6.4 6.8]. The mixture is stirred for 15 minutes ata ambient temperature and concentrated in vacuo. The residue is treated with cold water saturated with sodium chloride and extracted with chloroform (5-ml. 3X). The chlo roform solution is washed with water and saturated sodium chloride solution, then dried over anhydrous so dium sulfate. and concentrated in vacuo to give a yellow oil. This oil is chromotographed over silica gel by eluting with 2% methanol-98% chloroform mixtures to afiord S-chloro-I-](dipropylamino)methyll-6-phenyl- 4H-imidazol[ l,2-a][ l,4]benzodiazepine.

Example 46 8-Chloro-6-(o chlorophenyl l -[(methylamino methyl]-4H-imidazo[ l ,2-a][ l ,4]benzodiazepine A stirred suspension of 8-chloro-6-(o-chlorophenyl)- 1- dimethylamino )methyl ]-4H-imidazo[ l ,2- a][l.4]benzdiazepine (3.95 g, l0 mmole) and potassium bicarbonate l7 g, I? mmole) in 280 ml. of chloroform is treated with phenyl chloroformate (I297 g, 87 mmole) and refluxed for 50 hours. The resulting mixture is cooled, washed with water 100 ml) and the solvent is removed in vacuo. The residue is dissolved in 170 ml. of methanol and the resulting solution is treated with 100 ml. of 5.6 g of potassium hydroxide and 10 g of potassium bicarbonate. This mixture is stirred under nitrogen for 24 hours, acidified with concentrated hydrochloric acid, diluted with water, and extracted with 500 ml. of ether. The ether phase is dried over anhydrous sodium sulfate, and the ether is removed in vacuo. The thus obtained material is dissolved in a mixture of 800 ml. of ethanol and aqueous 50% potassium hydroxide (200 ml) and refluxed under nitrogen for 24 hours. This solution is treated with 200 ml. of concentrated hydrochloric acid and the ethanol is removed in vacuo. The remaining aqueous phase is extracted with ether, and the ether is discarded. The aqueous phase is then made basic, pH 9.0 and reextracted with methylene chloride (800 ml). The methylene chloride is dried over anhydrous sodium sulfate and the solvent is removed in vacuo. The resulting oil is crystallized to give 8-ehloro-6-(o-chlorophenyl)-l- [(methylamino )methyl]-4H-imidazo[ l ,2 a][ l ,4]benzodiazepine.

In the manner given in Example 46, other acid addition salts of l-[(methylamino)methyl]-6-phenyl-4H- imidazo[ l ,2-a]-[ l,4]benzodiazepines can be obtained. Representative compounds thus produced include: 8-chlorol -[(methylamino )methyl ]-6-phenyl-4H- imidazol l,2-a]-[ 1,4]benzodiazepine; 8-nitro l methylamino )methyl ]-6-phenyl-4H- imidazo[ l,2-a]-[ 1,4]benzodiazepine;

S-nitrol methylamino)methyl ]-6-(o-chlorophenyl 4H-imidazo[ l .2-a][ l,4]benzodiazepine; S-trifluoromethyll (methylamino )methyl l-o-phenyl- 4H-imidazo[ l,2-a][ 1,4]benzodiazepine; 8-trifluoromethyll methylamino )methyl ]-6-( ochlorophenyl )-4H-imidazo[ l ,2-

a[ l ,4]benzodiazepine;

8-fluorol methylamino)methyl ]-6-(ofluorophenyl)-4H-imidazo[ l,2-a][ l ,4]benzodiazepine; 8-chlorol methylamino )methyl ]-6-( 2.6-

a][ l ,41benzodiazepine;

a][ l ,4 ]benzodiazepine;

a][ 1,4 ]benzodiazepine;

8-bromo-1-[(methy1amino)methyl]-6-(ochlorophenyl )-4H-imidazo[ l,2-

a][ l,4]benzodiazepine;

7 chlorol -[(methylamin0)methyl ]-6-(oehlorophenyl )-4H-imidazo[ l ,2

a] l ,4lbenzodiazepine;

lO-trifl uoromethyll methylamino )methyl ]-6-( 2 ,6- difluorophenyl )-4H-imidazo[ 1 ,2-

a] l,4]benzodiazepine;

8-trifl uoromethyll -[(methylamino)mcthyl -6-( ofluorophenyl )-4H-imidazo[ l.2-a][ 1,4]bcnzodiazepine; and the like.

Example 47 (3-bromoacetonyl)amine, ethylene ketal XVll) A solution of (3-phthalimidoacetonyl)bromide, ethylene ketal (50 mmole) (Example 2) in absolute ethanol is stirred with hydrazine hydrate 200 mmole) during 20 hours in a nitrogen atmosphere. The white solid which precipitates is filtered and washed with ethanol. The ethanol filtrate and washings are combined, and distilled in vacuo and the resulting residue is distilled at 5658 C/0.05 mm Hg. to give 6.2 g of (3- bromoacetonyhamine, ethylene ketal as a viscous oil in, 1.499. NMR(CDCl;;). 54.10 (4H, singlet), 3.49 (2H, singlet), 3.00 (2H, singlet), 1.40 L78 (2H, broad singlet).

Example 48 7-Chloro-5-phenyl-2-[( 3-bromoacetonyl )amino]-3H- l ,4-benzodiazepine A suspension of 7-chloro-LB-dihydro-S-phenyl-ZH- 1,4-benzodiazepine-Z-thione (400 mg., 1.5 mmole) and (fl-bromoacetonyl) amine, ethylene ketal (900 mg., 4.5 mmole) in 30 ml. of absolute ethanol is heated at 60 for l8 hours while a stream of nitrogen is bubbled through the reaction mixture. After cooling to room temperature, the ethanol is taken off in vacuo to afford 500 mg. of yellow oil. This oil on trituration with anhydrous ether gives 200 mg. (30%) of white solid. The solid is filtered and the resulting filtrate is removed in vacuo. The residue is chromatographed over silica gel by eluting with 3% methanol-97% chloroform to afford mg I271) of 7-chloro-5-phenyl-2-[(3 bromoacetonyl )aminoI-3H- l ,4-benzodiazepine. An analytical sample crystallizes from ethyl acetate/hexane and has a melting point of 206-290C.

Anal. Calcd. for C- H BrCIN O mw 448.73: C, 53.53; H. 4.27; N, 9.37; Br, l7.8l; Cl, 7.90; Found: C. 53.23; H. 4.27; N, 9.51; Br, 17.84; Cl, 7.37.

Example 49 7-Chloro-5-phenyl-2-I 3-azidoacetonyl )aminol-3H- l,4-benzodiazepine, ethylene ketal A suspension of 7-chloro-5-phenyl-2- 3- bromoacetonyl )-amino ]-3H- l ,4benzodiazepine ethylene ketal (l0 mmole) and sodium azide (1.56 g, 24 mmole) in 25 ml. of dimethylsulfoxide is heated on a steam bath in a nitrogen atmosphere during 5 days. The mixture is then cooled. extracted with chloroform; the chloroform extracts are dried over anhydrous sodium sulfate and evaporated. The resulting product is recrystallized from ethyl acetate Skellysolve B (hexanes) to give 7-chloro-5-phenyl-2-( 3-azidoacetonyl )amino 3H-l.4-benzodiazepine. ethylene ketal, melting point 18l,5-l82.5C.

Example 50 7-Chloro-5-phenyl-2-[ [3-(dimethylamino1acctonyl]- amino]-3H-1.4-benzodiazepine, ethylene ketal A solution of 7-chloro-5-phenyl-2-[( 3- azidoacetonyl )-amino]-3H-l .4-benzodiazepine. ethylene ketal in ethyl acetate is hydrogenated in the presence of 1071 palladium on charcoal catalyst at room temperature for 3 hours at 50 psi of hydrogen. The reaction mixture is filtered and the filtrate evaporated to give crude 7-ch1oro-5-phenyl-2-[( 3- aminoacetonyl)aminol-3H-1,4-benzodiazepine. ethylene ketal which was immediately treated in acetonitrile solution, with 37% aqueous formaldehyde and sodium cyanoborohydride. followed by acetic acid to give 7- chloro-S-phenyl-2-[ 3- (dimethylamino )acetonyl ]amino]-3H-1 ,4- benzodiazepine, ethylene ketal as an oil.

Example 5 l 8-Ch1oro1-[(dimethylamin0)methyl]-6-pheny1-4H- imidazo[ l .2-a][ 1.4]benzodiazepine A suspension of 7-chloro-5-phenyl-2-[ 3- (dimethylamino)acetonyl]amino]-3H-1.4- benzodiazepine, ethylene ketal 1.5 mmole) is heated to 1 10 to 120 in diethylene glycol under nitrogen for hours. The above mixture is cooled and evaporated to dryness in vacuo leaving behind a white oil. This is crystallized from ethyl acetate/hexane to give 8-chlorol-[(dimethylamino )methyl ]-6-pheny1-4H-imidazo[ 1 .2- a]l1.4]benzodiazepine of melting point 18 ll 82C.

Example 52 (3-azidoacetonyl )amine, ethylene ketal A suspension of 3-phthalimidoacetonyl )azide. ethylene ketal (Example 3) 16 g. 56 mmole) and hydrazine hdyrate 12 g, 240 mmole) in 250 ml of absolute ethanol is stirred at room temperature under nitrogen overnight. A white precipitate separates and is removed by filtration. The filtrate is evaporated in vacuo and the residue is distilled under reduced pressure. The product distills at 6062/0.03-0. 10 mm Hg pressure to afford 4.2 g (48%) of (3-azidoacctonyl)amine, ethylene ketal as a clear white oil of 11,, 1.481.

Anal. Calcd. for C -,H ,N O- mw 158.17: C, 37.96; H. 6.37; N. 35.43. Found: C. 37.89; H. 6.30: N. 35.16.

Example 53 7-Chloro-5-phenyl-2-[( 3-azidoacetonyl )amino ]-3H- 1.4-benzodiazepine, ethylene ketal A suspension of 7-chloro-l,3-dihydro-5-phenyl-2H- 1.4-benzodiazepine-Z-thione (0.143 g, 0.5 mmole) and (3-azidoacetonyl)amine, ethylene ketal (0.240 g, 1.5 mmole) in 10 ml. of absolute ethanol is heated at 60C. for 4 hours while a stream of nitrogen is bubbled through the reaction mixture. After cooling to room temperature the reaction mixture is quenched in cold water and extracted with chloroform (3X. 50 ml. The chloroform extract is washed with water, saturated sodium choride solution and dried over anhydrous sodium sulfate. Evaporation of chloroform in vacuo and trituration of the residue with anhydrous ether affords 180 mg. (87%) of 7-chloro-5-phenyl-2-[( 3- azidoacetonyl )amino1-3H- l ,4-benzodiazepine. ethylene ketal of melting point l80-18S C. An analytical sample was recrystallized from ethyl acetate/hexane and had a melting point of l8l.5182.5 C.

Anal. Calcd. for C H ,,ClN.,-O mw 410.87: C. 58.46; H, 4.66; N, 20.46; Cl, 8.63. Found: C, 58.41; H. 4.69; N. 20.38; Cl. 9.00.

This product is converted as in Examples 50 and 51 to the final product 8-chloro- 1 [(dimethylamino)methyl ]-4H-imidazo[ 1.2-

a][ 1,4]benzodiazepine.

In the same manner shown in the alternative procedures. Examples 47 through 53, the other priordescribed l-[ (dialkylamino )alkyl ]-6-phcny1-4H- imidazo[ 1,2-a][ l ,41-benzodiazepines can be prepared.

Moreover the synthesis shown in the prior examples, when carried out with a 3-methyl-S-pheny1- l ,3- dihdyro-2H-1,4-benzodiazcpine-Z-thiones provide the corresponding l-[ dialkylamino )alkyl ]-4-methy1-6- phenyl-4H-imidazo[ l .2-a]-[ 1 ,4lbenz0diazepines. such as: 8-ch1orol -[(dimethylamino)methyl1-4-methyl-6- pheny1-4H-imidazol 1 ,2-a][ 1,4]benzodiazepine;

8-chlorol-[ dimethylamino )methyl ]-4-methyl-6-( ochlorophenyl)-4Himidazo[ 1.2-

a][ 1.4 ]benzodiazepine;

8-nitrol -[(dimethylamino)methyl l-4-methyl-6- phenyl-4H-imidazo[ l,2-a][ 1 .4lbenzodiazepine; 8-nitro-1-l (dimethylamino)methyl]-4-methyl-6-(ochlorophenyl )-4H-imidazo[ 1.2-

a 1.4]henzodiazepine;

S-trifluoromethyl- 1 dimethylamino )methyl ]-4- methyl-6-phenyl-4H-imidazo[ 1,2-

all 1,41benzodiazepine;

8-trifluoromethyll dimethylamino )methyl ]-4- methyl-6-( o-ehlorophenyl )-4H-imidazo[ 1.2-

a 1.4 ]henzodiazepine;

S-t'luorol dimethylamino )methyl]-4-methy1-6-(ochlorophenyl )-4H-imidazo[ 1.2-

a ]l 1 .4 lbenzodiazepine;

S-chlorol dimethylamino )methyl ]-4-methyl-6-( 2,6- difluorophenyl )-4H-imidazo[ 1 ,2-

all 1.4 ]benzodiazepine; 8-fluoro-1-|(dimethylamino)methyl]-4-methyl-6-(2.6- difluorophenyl)-4H-imidazo[1.2-

a H 1.4 lbenzodiazepine;

S-hromol (dimethylamino )methyl ]-4-methyl-6-(ochlorophenyl )-4H-imidazo[ 1.2-

a][ 1.4 lbenzodiazepine;

l (dimethylamino )methyl1-4-methyl-6-(ochlorophenyl )-4H-imidazol 1.2-

a ll 1 .4 ]benzodiazepine;

lll-trifluoromethyll dimethylamino )methyl ]-4- methyl6-(2.6-difluoropheny1)-4H-imidazo[ 1.2-

all 1.4]benzodiazepine; 8chl0ro-l [(methylamino )methyl ]-4-methy1-6-( o-chlorophenyl 4H-imidazol 1 .2-a 1.4}benzodiazepine;

8-nitrol -(methylamino)methyl1-4-methyl-6-phenyl- 4H-imidazol l,2-a][ 1.4]benzodiazepine;

8-nitrol methylamino )methyl ]-4-methyl-6-(ochlorophenyl )-4 H-imidazo[ 1.2-

a 1 .4 ]benzodiazepine; S-trifluoromethyl-1-l(methylamino)methyll-4-methyl- 6-phenyl-4H-imidazo[ 1.2-all 1.4]benzodiazepine; 8-trifl uoromethyll-[ methylamino)methyl ]-4-methyl- 6-( o-chlorophenyl )-4H-imidazo[ 1 .2-

a][ 1,4 ]henzodiazepine;

8fluorol-[ methylamino )methyl ]-4-methyl-6-( ochlorophenyl )-4H-imidazo[ 1.2-

a][ 1.4 ]benzodiazepine;

l'l-chlorol-[ methylamino )methyl ]-4-methyl-6-( 2.6- difluorophenyl )-4H-imidazo[ 1.2-

a l ,4 lbenzodiazpine;

a][ 1,4]benzodiazepine;

9-bromol methylamino )methyl -4-methyl-6-( ochlorophenyl )-4H-imidazo[ l ,2-a[ l ,4]benzodiazpine; 7-chloro- -[(methylamino )methyl ]-4-methyl-6-( ochlorophenyl )-4H-imidazo[ l ,2-

al l .4 ]benzodiaz'epine;

lO-trifluoromethyll -[(methylamino)methyl1-4- methyl-6-( 2,6-difluorophenyl )-4H-imidazo[ 1.2-

all l.4]benzodiazepine;

and the like.

[he pharmacologically acceptable acid addition salts of compounds of formula XXIV (including XXIVA. XXlVB, and XXlVC) can he prepared and isolated by conventional processes, such as reacting a compound of formula XXIV with a selected pharmacologically acceptable acid. Such acids include hydrochloric, hydrohromic. phosphoric, sulfuric. acetic. tartaric, lactic, citric. malic, maleic, methanesulfonic, benzenesulfonic, cyclohexanesultamic acids. toluenesulfonic, and the like. The reaction is conveniently performed in an organic solvent. e.g., ether, dioxane or tetrahydrofuran, ethanol. methanol, ethyl acetate; the salts can be recovered by crystallization. precipitation or evaporation of the solvent. These salts are useful in the same manner as the free base.

I claim:

1. A compound of the formula:

RI H O wherein R R R and R are hydrogen or methyl; wherein R',; is hydrogen, chloro or fluoro; wherein R is hydrogen or fluoro; wherein R is hydrogen. chloro. fluoro or trifluoromethyl and the pharmcologically acceptable acid salts thereof.

3. A compound of the formula:

wherein R and R are hydrogen or methyl; wherein R";, is hydrogen or chloro; wherein R";, is chloro or fluoro. and the pharmacologically acceptable acid salts thereof.

4. A compound according to claim 3, wherein R R and R";. are hydrogen. R" is chloro. and the compound is therefore l-aminomethyl-8-chloro-6-phenyl- 4H-imidazol I .2-a][ 1.4]benzodiazepine.

S. A compound according to claim 3, wherein R and R,- are methyl, R";, is hydrogen. R; is chloro. and the compound is therefore l-[(dimethylamino)methyl1-8- chloro-6-phenyl-4H-imidaz0[ l ,2-

a][ 1 ,4lbenzodiazepine.

6. A compound according to claim 3, wherein R and R are methyl; R" and R";, are chlorine and the compound is therefore l-[(dimethylarnino)methyl]-8- chloro-o-(o-chlorophenyl )AH-imidazol l .2-

a l,4 ]benzodiazepine.

7. A compound according to claim 3, wherein R and R are methyl, R";, is hydrogen, R"; is trifluoromethyl and the compound is therefore I [(dimethylamino )methyl ]-8-trifluoromethyl-6-phenyl- 4H-imidazo[ l .2-a)[ l .4]benzodiazepine.

8. A compound according to claim 2, wherein R and R; are methyl. R',,, R' R',,, and R are hydrogen, R';, is fluoro, and the compound is therefore l [(dimethylamino )-methyl ]-8-fluoro-6phenyl-4H- imidazol l .2-a][ l,4]benzodiazepine.

9. A compound according to claim 2, wherein R,; and R are methyl, R',,. R' R';, are hydrogen. R' is nitro, and the compound is therefore [(dimethylamino )methyl l 8-nitro-6-phenyl-4H- imidazo] l .Z-a 1.4Ibenzodiazepine 10. A compound according to claim 2. wherein R and R are methyl; wherein R',, and R'. are hydrogen; wherein R'.-, is chloro; wherein R' and R. are fluoro and the compound is therefore llldimethylamino)methyll-S-chloro-fi-l1.6 difluorophenyl )-4H-imida7.o[ L2- I]. A compound according to claim 2, wherein R. and R are methyl; wherein R',, is methyl; wherein R is hydrogen; wherein R';, is chloro; wherein R1; is chloro and R. is hydrogen and the compound is therefore l-[ dimethylamino )methyl l-2 methyl-X-chloro-fi- (o-chlorophenyl l-4H-imidazol 1.2- all l.4]benzodia7.epine. 

1. A COMPOUND OF THE FORMULA
 2. A compound of the formula:
 3. A compound of the formula:
 4. A compound according to claim 3, wherein R6, R7, and R''''3 are hydrogen, R''''5 is chloro, and the compOund is therefore 1-aminomethyl-8-chloro-6-phenyl-4H-imidazo(1,2-a)(1, 4)benzodiazepine.
 5. A compound according to claim 3, wherein R6 and R7 are methyl, R''''3 is hydrogen, R''''5 is chloro, and the compound is therefore 1-((dimethylamino)methyl)-8-chloro-6-phenyl-4H-imidazo(1,2 -a)(1,4)benzodiazepine.
 6. A compound according to claim 3, wherein R6 and R7 are methyl; R''''3 and R''''5 are chlorine and the compound is therefore 1-((dimethylamino)methyl)-8-chloro-6-(o-chlorophenyl)-4H-imidazo(1,2 -a)(1,4)benzodiazepine.
 7. A compound according to claim 3, wherein R6 and R7 are methyl, R''''3 is hydrogen, R''''5 is trifluoromethyl and the compound is therefore 1-((dimethylamino)methyl)-8-trifluoromethyl-6-phenyl-4H-imidazo(1,2 -a)(1,4)benzodiazepine.
 8. A compound according to claim 2, wherein R6 and R7 are methyl, R''o, R''2, R''3, and R''4 are hydrogen, R''5 is fluoro, and the compound is therefore 1-((dimethylamino)-methyl)-8-fluoro-6-phenyl-4H-imidazo(1,2 -a)(1,4)benzodiazepine.
 9. A compound according to claim 2, wherein R6 and R7 are methyl, R''o, R''2, R''3 are hydrogen, R''5 is nitro, and the compound is therefore 1-((dimethylamino)methyl)-8-nitro-6-phenyl-4H-imidazo)1,2 -a)(1,4)benzodiazepine.
 10. A compound according to claim 2, wherein R6 and R7 are methyl; wherein R''o and R''2 are hydrogen; wherein R''5 is chloro; wherein R''3 and R''4 are fluoro and the compound is therefore 1-((dimethylamino)methyl)-8-chloro-6-(2,6-difluorophenyl)-4H-imidazo(1,2 -a)(1,4)benzodiazepine.
 11. A compound according to claim 2, wherein R6 and R7 are methyl; wherein R''o is methyl; wherein R''2 is hydrogen; wherein R''5 is chloro; wherein R''3 is chloro and R''4 is hydrogen and the compound is therefore 1-((dimethylamino)methyl)-2-methyl-8-chloro-6-(o-chlorophenyl)-4H -imidazo(1,2-a)(1,4)benzodiazepine. 